慢性C型肝炎病毒感染者於接受長效型干擾素和 雷巴威林合併治療前後之早期病毒動力學變化

Abstract

背景與目的：C型肝炎病毒感染一直是西方國家公共衛生上的重要課題，在台灣地區則僅次於B型肝炎病毒的感染排名為第二位。因此如何將C型肝炎病毒感染的影響與傷害性減到最低在目前台灣的醫療與公共衛生是相當重要的。 臨床上最有效並且被列為標準的C型肝炎的治療方法為長效型干擾素與口服雷巴威林的合併療法。但是有高達75%的病人在合併療法下會有不良反應發生，甚至需要藥物減量以及停止治療。因此如何使治療效果更加完美，縮短治療療程以減少不良反應，並且使用在最適當的病人身上就格外重要。 許多臨床因素會影響到干擾素相關治療的效果。針對不同種族治療效果的研究中，國外的學者發現非洲裔美國人比美國白種人對於傳統型干擾素相關治療的反應較差。病毒動力學的研究上也發現：非洲裔美國人在抑制已受感染之肝臟細胞的病毒製造能力上表現較差，因此對於治療的反應比較不好。最近的研究報告也指出非洲裔美國人對於長效型干擾素合併治療的效果比非西班牙裔的白種人要差。值得注意的是，台灣進行的前瞻性長效型干擾素的治療研究發現：台灣C型肝炎病毒1b基因型的患者，接受長效型干擾素合併治療半年後的療效與歐美白種人患者治療一年的療效相當。這個現象引起了吾人極大的研究興趣，想要找出引起這種治療效果差異的原因。 另一方面，臨床研究發現藉由病人接受治療時的早期病毒動力學變化資料，可以準確預測出病人將來對於干擾素相關治療的療效；然而有關病毒動力學的資料大部分都是來自於國外，國內C型肝炎病毒對於抗病毒藥物治療的相關動力學資料並不清楚。而且大部分治療時的病毒動力學資料都是使用傳統型干擾素治療後所得到的結果，對於使用長效型干擾素來治療時的早期病毒動力學資料並不多。因此吾人希望能夠深入了解國內C型肝炎病毒感染者在接受長效型干擾素和雷巴威林合併治療前後的病毒動力學變化，並且與國外已知的資料相比較，看看是不是有所差異以及差異在哪裡？

材料和方法：吾人收集6位18歲(含)以上，超過六個月以上未飲酒且以前未經干擾素治療的慢性C型肝炎感染患者, 先行接受一周單一劑量的長效干擾素注射測試，於第二周時再開始接受為期24周的長效干擾素和口服雷巴威林之合併治療。藉由分析接受長效型干擾素合併治療的慢性C型肝炎病毒感染患者血清之核醣核酸定量、定性資料與ALT值，以及國外學者所提出的干擾素相關治療時病毒動力學變化模式，佐以數學統計和相關的參數分析來評估病毒動力學變化。並於治療結束後24周時檢驗血清中C型肝炎病毒核醣核酸，以C型肝炎病毒核醣核酸的定性檢驗結果作為治療成效的判定。 結果：所有接受長效型干擾素合併治療的病人都有達到早期病毒反應，並且在第十四周時所有的患者病毒量都在100 copies/mL以下。追蹤至第33周時有一位病人再度復發。所有患者的ALT值皆隨治療過程而逐漸降低。六位患者在第40周時之生化反應率達到83.3%。除了一位患者因為病毒量太低無法被用來計算參數之外，其他五位患者的ε參數在0.4128至0.9904之間。δ參數數值在0.00195至0.1245之間。所得兩種參數的結果值與國外的報告相類似。 結論：雖然參數的分析上我們目前無法得到明確的結果，但是由吾人的研究結果可以顯示：國人在開始接受治療後之前4周的病毒量下降程度較白種人為大，特別是在前2天內的病毒量下降幅度更大。這暗示著國人對於治療效果較好的可能因素之作用時間主要在治療開始後的前兩天；另一個可能的解釋則為國人患者中對於治療效果較好的亞族群所占的比率可能相對較高。 吾人由本研究觀察到台灣C型肝炎病毒感染患者在接受長效型干擾素和雷巴威林合併治療後之早期病毒動力學與ALT值的可能變化狀態，對於改善國內慢性C型肝炎病毒感染患者的治療反應和預後，減少治療過程不良反應的發生，並且提早找出最需要與最適合於治療的病人族群方面皆有深遠的影響。

Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma in the western world. In Taiwan, 80% to 90% of chronic liver diseases are caused by hepatitis B virus infection and HCV is the second common cause of these diseases. Combination therapy with pegylated interferon and ribavirin is the current standard treatment for chronic hepatitis C and able to eradicate virus in more than 40% of genotype 1 infected patients and more than 76 % of non-genotype 1 patients. Due to the expense and the adverse events of combination therapy, identification of patients who will not respond is desirable in order to stop the treatment and save money. Western studies have suggested that early viral kinetics following initiation of antiviral therapy may be worthwhile and remain a milestone to assess the need for continued treatment. Pilot studies in Taiwan have suggested that Taiwanese patients with chronic hepatitis C virus infection respond better than white patients. Thus we designed this study to examine the early viral kinetic response of hepatitis C virus (HCV) in Taiwanese chronic hepatitis C patients receiving pegylated interferon alfa and ribavirin combination therapy for 6 months. Methods: Six chronic hepatitis C patients were prospectively collected from the outpatient clinic of the National Taiwan University Hospital. They all received peginterferon alfa in combination with ribavirin for 24 weeks, and were follow-up for another 24 weeks. Serum HCV RNA levels were checked quantitatively and frequently during the first day after initiation of peginterferon alfa therapy. The viral loads were then monitored quantitatively everyday for 3 days, every week for 4 weeks, every 2 weeks for 4 weeks and every month for 3 months. After 24 weeks of follow-up, serum HCV RNA level was qualitatively assayed to determine the sustained virological response. The kinetic parameters (ε, treatment effectiveness at inhibiting viral production; δ, loss rate of virus-producing cells) were estimated from the viral load decay profiles by using a mathematical model. Results: There were 4 patients infected with HCV genotype1 and 3 with genotype 2. Mixed infection with both genotype 1 and 2 was found in one patient. All of there serum HCV RNA levels became undetectable at week 12 and only one patient relapsed at week 33. The ε was between 0.4128 to 0.9904 and δ was between 0.0019 to 0.1245. The differences in viral load between day 7 and 14 were observed in three patients, and the log values of the differences were 0.15, 0.66 and 1.21 respectively. Half of the patients’ serum ALT levels returned to normal range at week 24 and only one still had abnormal ALT level at week 40. Conclusions: This is the first early HCV kinetic study on chronic hepatitis C patients with pegylated interferon-based therapy in Taiwan. Although no significant differences were found between our kinetic parameters and previous reports, the viral decline pattern and viral negativity rates at early viral kinetic stage of Taiwanese patients seems to be different from Caucasian patients. This study gave us some clues about the possible underlying mechanisms of the differences between races, and let us more close to the goal of ideal therapy for chronic hepatitis C.